J. Hürlimann

The site of formation of C-reactive protein (CxRP, CRP) has been studied with tissues from rabbits, monkeys, and human beings. Rabbits and monkeys were stimulated to produce the acute phase protein by injection of turpentine, croton oil, endotoxin, paratyphoid-typhoid vaccine, or pneumococci. C(14)-amino acid incorporation in vitro was demonstrated by means of autoradiography of immunoelectrophoretic patterns made with culture fluids. It was found that among many different tissues tested liver was the only tissue which incorporated C(14)-lysine and isoleucine into CxRP or CRP. Only livers taken 16 to 24 hr after various stimuli were active; livers from normal animals or from animals killed 3 to 9 hr after stimulation did not produce detectable amounts of CxRP. Inflamed muscle from the injection site did not show C(14)-amino acid incorporation into CxRP. Several human tissues were also cultured, and a few liver cultures found to contain labeled CRP. The formation of CxRP or CRP by the liver was always accompanied by enhanced C(14)-amino acid incorporation into other serum proteins, but the reverse was not always found.

The cause, or causes, of the vast majority of Alzheimer's disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD.

Immunohistochemical techniques were used to study 177 hepatic tumors (hepatocarcinoma, cholangiocarcinoma, hepatocholangiocarcinoma, adenocarcinoma of unknown origin, and metastatic carcinoma). Phenotypes suggestive of hepatocarcinoma included keratins 8 and 18, factor XIII a, alpha-fetoprotein. C-reactive protein, carcinoembryonic antigen (CEA) cross-reacting antigen; those in effect that excluded hepatocarcinoma were keratins 1, 5, 10, 11, 19, true CEA. C-reactive protein, used for the first time, proved to be a fairly sensitive and specific marker. Factor XIII a, which was thought to be synthesized only by histiocytes, was also present in hepatocytes. Immunohistochemistry appears to be an important tool in the diagnosis of hepatic tumors. As a result of this study, 32 cases were reclassified; several were found to be intermediate between hepatocarcinoma and cholangiocarcinoma. Sixteen cases apparently were true hepatocholangiocarcinomas. In 12 cases of hepatocarcinoma, some tumor cells expressed keratins of bile duct type. It was impossible to differentiate immunohistochemically cholangiocarcinoma from metastatic carcinoma, except in two cases with breast tissue markers.

Tumor-infiltrating lymphocytes (TIL) were obtained by a combination of mechanical release and enzymatic disaggregation from 35 human solid tumors. The number of lymphocytes in TIL-enriched suspensions varied from 1 X 10(4) to 7.6 X 10(6) per wet gram of tumor. The TIL preparations separated by differential centrifugation on Ficoll-Hypaque gradients contained 10-95% of T11+ cells (mean 50%), and tumor cells accounted for the other major cellular component. Macrophages, NK cells, B cells and granulocytes were infrequently seen. Morphologically, TIL-T were small non-activated cells. They expressed the T11 and T3 antigens but not the receptor for IL-2 (IL-2R) or HLA-DR antigens as determined by double immunofluorescence staining. Rare T11+/IL-2R+ cells were recovered only from colon and lung carcinomas. The mean T4/T8 ratio in 12 TIL preparations was 1.1 +/- 0.8. Immunohistology with monoclonal antibodies (MAbs) performed in 31/35 tumors confirmed that the T11+ cells infiltrating solid tumors rarely expressed the IL-2R and that the cell content of suspensions enriched in TIL was comparable to that determined in situ. The recovered TIL were cloned in a microculture system that permits proliferation of nearly all normal peripheral blood T lymphocytes (PBL-T). Under these culture conditions, frequencies of the proliferating T lymphocyte precursors (PTL-P) were depressed in both the TIL preparations (less than 0.01 to 0.39) and patients' PBL-T (0.05 to 0.5). These low frequencies of PTL-P were seen in patients with all tumor types, both primary and metastatic.

The high plasma cortisol and ACTH levels present in pregnant women as well as the non-parrallelism of their plasma extract dilution curves in comparison with the standard curve in the ACTH radioimmunoassay, are evidence for the presence of an ACTH-like substance during pregnancy which would interfere with the assay. Placental extracts were obtained by acid-acetone extraction, followed by partial purification with oxycellulose and by extraction with porous glass powder. A substance was detected which partially cross-reacted with synthetic human ACTH in the radioimmunoassay and which showed biological activity using the assay procedure described by Liscomb & Nelson. The data sustain the existence of an ACTH-like placental hormone: human chorionic corticotrophin (HCC).